Use of diphenylbutyl-piperazinecarboxamides in the treatment of substance disorders

ABSTRACT

The present invention relates to the relief or prevention of withdrawal syndrome resulting from addiction to alcohol and/or the suppression of dependence on alcohol by administering to a person in need thereof, an effective amount certain diphenylbutyl-piperazine-carboxamides including 4-[4,4-bis(4-fluorophenyl)butyl]-N-ethyl-1-piperazine-carboxamide which is also known as amperozide.

FIELD OF THE INVENTION

The present invention relates to a new use of certaindiphenylbutyl-piperazinecarboxamides, especially amperozide,4-[4,4-bis(4-fluorophenyl)butyl]-N-ethyl-1-piperazinecarboxamide, andsalts thereof, in the treatment of substance abuse disorders. Moreparticularly, this invention relates to the amelioration of withdrawalsymptoms and to modifying drug-seeking behaviour.

BACKGROUND OF THE INVENTION

Different classes of neuronal receptors and neurotransmitters in thebrain have been implicated in the complex mechanisms underlying thecompulsive drinking of alcohol. Experimental findings have favoured theopioid, dopaminergic, serotonergic, and benzodiazepine receptorsubtypes. Whether the receptor category is pre- or postsynaptic innature and whether neurotransmitter synthesis and/or release is equallyinvolved in the manifestation of alcohol drinking is presently unknown.

Drug dependency is extremely difficult to escape. This is true whetherthe dependency is one based on ethanol, amphetamine, barbiturates,benzodiazepines, cocaine, nicotine, opioids, and phencyclidine or thelike. Despite active research, there are as yet no drugs thatspecifically can antagonize for example the alcohol craving inalcohol-dependent subjects. Previous research demonstrated that forexample serotonin uptake blockers (e.g. zimelidine, sertraline) reducevoluntary alcohol consumption in rats and humans. However, the mechanismof action of these compounds is not Well understood. There isconsiderable experimental evidence that the effects on alcohol intakemay be an expression of a more general inhibiting role that serotoninplays in consummatory behaviour. Indeed serotonin uptake blockers andserotonin agonists have been shown to reduce a number of oralconsummatory behaviours such as the intake of food as well as a varietyof flavoured fluids such as alcohol.

The serotonin uptake blocker, sertraline, has been found to reducealcohol intake in rats. Concurrent with the effect on alcohol drinking,however, sertraline lowered the intake of food and water and caused anoverall decline in body weights (Gill K. et al., Alcohol 5:355-358,1988; Myers R. D. and Quarfordt S. D., Pharmacol. Biochem. Behav.40:923-28, 1991). Clearly, it is likely that the action of sertraline onalcohol intake is related to a serotonin uptake blocker's effect on oralconsummatory behaviour. Hence, a decline also in the drinking of alcoholwould not be unexpected. Furthermore, during the period following thesertraline treatment, the intake of alcohol rose toward the pretreatmentlevel. There is accordingly a need for a more specific and effectiveagent to be used for treating abuse disorders.

SUMMARY OF THE INVENTION

It has now unexpectedly been found thatdiphenylbutyl-piperazinecarboxamides of the formula ##STR1## wherein

R₁ and R₂ are groups independently selected from the group of H, alkylchains, straight or branched, with 1-10 carbon atoms, cycloalkyl with3-8 carbon atoms, aralkyl with 7-9 carbon atoms, alkenyl with 2-10carbon atoms, phenyl unsubstituted or substituted by one to three groupsselected from halogen, especially F, Cl and Br, lower alkyl with 1-5carbon atoms, lower alkoxy with with 1-5 carbon atoms, amineunsubstituted or substituted by one or two lower alkyl groups with 1-5carbon atoms, --CF₃ and --CN groups,

R₃, R₄, R₅ and R₆ are groups independently selected from H, lower alkylhaving from 1-3 carbon atoms and phenyl,

R₇ is selected from hydrogen, halogen especially F, Cl and Br, loweralkoxy with 1-3 carbon atoms and --CF₃, and

X is O or S and pharmaceutically acceptable salts thereof,

are extremely effective and specific in suppression of alcoholdependence.

This finding opens up a completely new method of treating dependence ondrugs, alcohol, nicotine and the like. The actual substances have beenfound to be both chemically and pharmacologically different from thosedrugs suggested hitherto for the treatment of drug dependence.

Specifically the invention relates to the relief or prevention of awithdrawal syndrome resulting from addiction to a drug or substance ofabuse and/or for the suppression of dependence on drugs or substances ofabuse.

The substances as such are known from the prior art (see U.S. Pat. No.4,308,387, which is hereby incorporated by reference) as well as theiruse use in other areas of medicine (see U.S. Pat. Nos. 4,447,433,4,385,057 and 5,013,735).

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a method for treating substance abusedisorders by administering to a patient suffering from abuse atherapeutically effective amount of adiphenylbutyl-piperazinecarboxamide according to Formula I, as definedabove. The at present preferred substances are those wherein

R₁ is methyl, ethyl or n-, iso- or cyclopropyl,

R₂ is H,

R₃, R₄, R₅ and R₆ are hydrogen or R₃ and R₆ are hydrogen and R₄ and R₅are methyl, or R₄ and R₅ are hydrogen and R₃ and R₆ are methyl,

R₇ is hydrogen or halogen, preferrably one substituent on each benzenering being F, and

X is O,

or physiologically acceptable salts thereof.

The most preferred substance at present is amperozide or aphysiologically acceptable salt thereof. Amperozide, with the chemicalname 4-[4,4-bis(4-fluorophenyl)butyl]-N-ethyl-1-piperazinecarboxamide,is a psychotropic compound developed by Bjork A.K.K. et al (U.S. Pat.No. 4,308,387) with effects preferentially on emotional behaviourmediated by an action on the limbic brain areas (Christensson E. andBjork A., Pharmacol. Toxicol. 66: Suppl. I, 5-7, 1990). While themechanism by which amperozide affects emotional behaviour remainsunknown, research indicates that amperozide is a serotonergic antagonist(Svartengren J. and Simonsson P., Pharmacol. Toxicol. 66: Suppl. I,8-11, 1990) and, furthermore, acts as a serotonin uptake blocker(Eriksson E., Life Sci. 47:2111-2117, 1990). Recent findings suggestthat amperozide modifies also the glutaminergic neurotransmission thatwould be of importance for learning and memory.

In said article by Eriksson E., a statement is cited telling that"serotonin uptake inhibitors might be useful in the treatment of abuse,e.g. citalopram and zimelidine, which appear to suppress the abuse foalcohol". However, there is in said article no mention of the fact thatserotonin uptake blockers have been shown to reduce a number of oralconsummatory behaviours. Apparently, a serotonin uptake blockade doesnot in itself constitute the basis for a pharmacological specificity ofaction in the treatment of substance abuse disorders. Hence, the generalstatement in said article by Eriksson E. does not give a man of ordinaryskill in the art the basis for selecting substances which meet the needfor more specific and effective agents to be used in the treatment ofsubstance abuse disorders.

The invention is also related to the use of a therapeutically effectiveamount of a substance according to Formula 1 for preparation of acomposition for the treatment of substance abuse disorders, as well asto the composition as such.

Repeated administration to a subject of certain drugs such as opiates,(e.g. morphine), cocaine, benzodiazepines (e.g. diazepam), or substancesof abuse such as alcohol or nicotine can lead to physical and/orpsychological dependence upon that drug or substance. When the drug orsubstance of abuse is withdrawn from a dependent subject, the subjectdevelops certain symptoms including sleep and mood disturbance andintense craving for the drug or substance of abuse. These symptoms maybe collectively described as a withdrawal or abstinence syndrome inconnection with the present invention.

Formulations comprising the pharmacologically active compounds of thisinvention are disclosed in U.S. Pat. Nos. 4,308,387, 4,385,057, and5,013,735 which are hereby incorporated by reference. As examples ofsuch formulations, expected to be suitable for use for treatment ofsubstance abuse disorders, can be mentioned:

Capsules containing (per capsule):

    ______________________________________                                        active ingredient      10     mg                                              lactose                250    mg                                              starch                 120    mg                                              magnesium stearate     5      mg                                              ______________________________________                                    

Tablets containing (per tablet):

    ______________________________________                                        active ingredient      10     mg                                              avicel                 108    mg                                              colloidal silica       10     mg                                              talc                   20     mg                                              magnesium stearate     2      mg                                              ______________________________________                                    

Injection solution (per 100 ml):

    ______________________________________                                        active ingredient      1000   mg                                              metagin                100    mg                                              NaCl                   700    mg                                              HCl 0.1N to pH 3.5                                                            Aq. sterilisata ad     100    ml                                              ______________________________________                                    

A therapeutically effective amount, expressed in mg per day, of thesubstance defined above, for instance amperozide, for use in thetreatment of substance abuse disorders, would be from about 0.1 to about40 mg, preferrably 0.1 to 20 mg, and especially 1-20 mg, depending onthe specific condition to be treated, the age and weight of the specificpatient and the specific patient's response to the medication. The exactindividual dosage, as well as the daily dosage, will accordingly bedetermined according to standard medical principles under the directionof a physician. The animal tests referred to below have indicated thatadministration twice a day gives a therapeutical effect, and this wouldbe expected to be the case also when the substance is administered to ahuman being.

The active ingredient may accordingly be expected to be administered toa patient in need of such treatment according to usual routes ofadministration and in usual forms. These include solutions, suspensions,emulsions, tablets, capsules, and powders prepared in pharmaceuticallyacceptable carriers for oral administration or sterile solution forparenteral administration.

In one embodiment of the invention the daily dose of the activesubstance is administered continuosly at a substantially constant level,over a given time period, for instance by an injection port or pump.

Various additives to enhance the stability or ease of administration ofthe drug are contemplated. The pharmaceutical composition may alsocontain additional therapeutically useful substances other than thepharmacologically active compounds of this invention for combinationtreatment.

Twenty years of research has consistently demonstrated that drugs thatare abused by man are usually self-administered by laboratory animals.Ethanol, amphetamine, barbiturates, benzodiazepines, cocaine, nicotineopioids, and phencyclidine and the like are just a few examples ofsubstances abused by man and self-administered in animal models. Thevalue of animal models for investigating the pharmacological andbehavioural mechanisms underlying drug dependence has been repeatedlydemonstrated. In fact, the animal models are our only recourse for theinvestigation of compounds to ameliorate or modify drug-seekingbehaviour. In relation to this there is considerable experimentalevidence supporting that a commonalty in the mechanism of the addictiveprocess itself exists in the brain stem which underlies the predilectionto abuse the above mentioned drugs.

The following examples are intended to illustrate the present inventionwithout in any way limiting the scope thereof:

EXAMPLE 1 Preparation of an Amperozide Tablet

Amperozide tablets were prepared having the following composition:

    ______________________________________                                        Amperozide hydrochloride                                                                              5.0    mg                                             Lactose                 105.5  mg                                             Microcrystalline cellulose                                                                            13.0   mg                                             Sodium Starch Glycolate 5.2    mg                                             Silicone Dioxide        0.65   mg                                             Magnesium Stearate      0.65   mg                                             ______________________________________                                    

The core composition was coated with a conventional sucrose coating togive a tablet for oral use.

EXAMPLE 2 The Effect of Amperozide on Cyanamide-induced Alcohol Drinkingin Rats

The effect of amperozide administered systemically was determined inSpraque-Dawley rats induced to drink alcohol chronically by a series ofintraperitoneal injections of cyanamide according to experimentalprocedures described previously (Critcher E. C. and Myers R. D., Alcohol4:347-353, 1987). Intake of food and water and measures of body weightgain were recorded.

Amperozide given subcutaneously in a dose of 2.5 mg/kg b.i.d. over athree-day interval markedly altered the volitional consumption ofalcohol. An immediate effect occurred following the administration ofamperozide in terms of both absolute amount in g/kg and proportion ofalcohol to water. The mean g/kg intake was reduced (P less than 0.01) byabout 60% from the pretest level 4.4 g/kg to 1.6 g/kg of alcohol. Theproportion of alcohol to total fluid consumed was similarly reduced fromthe pretest level. Of special importance is the fact that there were nosignificant effects produced by amperozide in terms of a change in thebody weight or in the amounts of food and water consumed by the ratsduring the treatment period in comparison with the pretest level,demonstrating a pharmacological specificity of action of this drug.

Particularly notable is the finding that amperozide administered in asteady state dose regimen by an Alzet osmotic minipump implanted in theintrascapular space in a dose of 5 mg/kg/day for seven days attenuatedsignificantly alcohol drinking in the cyanamide-treated rat in terms ofboth absolute g/kg and proportion of alcohol to water. In respect of theabsolute intake of alcohol, the mean g/kg ingested decreased (P lessthan 0.01) from 7.0 g/kg to 3.4 g/kg of alcohol during the delivery ofamperozide. In the four-day period following the systemicallyadministered amperozide, i.e. after the minipump was depleted of thedrug, the absolute g/kg intake of the rats was still suppressed.Moreover when the preference pattern was retested at 30, 70, 110 and 140day intervals following the cessation of amperozide delivery the declinepersisted. Concurrent with the effect on alcohol drinking, theconsumption of food as well as level of body weight was unaffected byamperozide. These results with amperozide provide the firstdemonstration of an enduring action of any drug on aberrant alcoholdrinking and clearly demonstrate that the actual compounds are usefulfor preventing or reducing dependency on dependency-inducing agents.

We claim:
 1. A method for the relief or prevention of a withdrawalsyndrome resulting from addiction to alcohol and/or for the suppressionof dependence on alcohol which comprises administering an effectiveamount of a diphenylbutyl-piperazinecarboxamide of the formula ##STR2##wherein R₁ and R₂ are groups independently selected from the group of H,alkyl chains, straight or branched, with 1-10 carbon atoms, cycloalkylwith 3-8 carbon atoms, aralkyl with 7-9 carbon atoms, alkenyl with 2-10carbon atoms, phenyl unsubstituted or substituted by one to three groupsselected from halogen, lower alkyl with 1-5 carbon atoms, lower alkoxywith with 1-5 carbon atoms, amine unsubstituted or substituted by one ortwo lower alkyl groups with 1-5 carbon atoms, --CF₃ and --CN groups,R₃,R₄, R₅ and R₆ are groups independently selected from H, lower alkylhaving from 1-3 carbon atoms and phenyl, R₇ is selected from hydrogen,halogen lower alkoxy with 1-3 carbon atoms and --CF₃, and X is O or S,or a physiologically acceptable salt thereof.
 2. A method according toclaim 1 whereinR₁ is methyl, ethyl or n-, iso- or cyclopropyl, R₂ is H,R₃, R₄, R₅ and R₆ are hydrogen or R₃ and R₆ are hydrogen and R₄ and R₅are methyl, or R₄ and R₅ are hydrogen and R₃ and R₆ are methyl, R₇ ishydrogen or halogen, and X is O.
 3. A method according to claim 2,wherein the diphenylbutylpiperazinecarboxamide is4-[4,4-bis(4-fluorophenyl)butyl]-N-ethyl-1-piperazinecarboxamide or aphysiologically acceptable salt thereof.
 4. A method according to claim3, wherein the diphenylbutylpiperazinecarboxamide is administered in adaily dose of from 0.1 to 40 mg.